Piperidine derivative and pharmaceutical composition

ABSTRACT

A novel piperidine derivative is defined by the formula (I), including a salt thereof, ##STR1## wherein R 1  denotes anthraquinone, X denotes a group of the formula --(CH 2 ) n  --, a group of the formula --O(CH 2 ) n  --, a group of the formula --S(CH 2 ) n  --, a group of the formula --NH(CH 2 ) n  --, a group of the formula --SO 2  NH(CH 2 ) n  --, a group of the formula ##STR2## a group of the formula ##STR3## a group of the formula ##STR4## a group of the formula --CH 2  NH(CH 2 ) n  --, a group of the formula ##STR5## (in all the above formulas, n is an integer of 1 through 7 and R 3  represents a lower alkyl group or a benzyl group), a group of the formula ##STR6## a group of the formula ##STR7## a group of the formula --O--CH 2  CH 2  CH═ or a group of the formula ##STR8## the ring A denotes a group of the formula ##STR9## a group of the formula ##STR10## a group of the formula ##STR11## or a group of the formula ##STR12##

This is a division of Ser. No. 07/811,698, filed Dec. 20, 1991 now U.S.Pat. No. 5,300,720, which is a division of Ser. No. 07/679,769, filedApr. 3, 1991 now U.S. Pat. No. 5,118,684, which is a division of Ser.No. 07/479,948, filed Feb. 14, 1990, now U.S. Pat. No. 5,039,681, issuedAug. 13, 1991, which is a division of Ser. No. 07/321,624, filed Mar.10, 1989, now U.S. Pat. No. 4,942,169, issued Jul. 17, 1990, which is adivision of Ser. No. 06/946,459, filed Dec. 24, 1986, now U.S. Pat. No.4,849,431, issued Jul. 18, 1989.

The present invention relates to piperidine derivatives having excellentactions as medicines. The invention relates more particularly topiperidine derivatives of the following general formula (I) orpharmacologically allowable salts thereof: ##STR13## wherein R¹ denotesa univalent group derived from one selected among substituted orunsubstituted benzene, pyridine, pyrazine, indole, anthraquinone,quinoline, substituted or unsubstituted phthalimide, homophthalimide,pyridinecarboxylic acid imide, pyridine N-oxide, pyrazinedicarboxylicacid imide, naphthalenedicarboxylic acid imide, substituted orunsubstituted quinazolinedione, 1,8-naphthalimide, bicyclo[2.2.2]octo-5-ene-2,3-dicarboxylic acid imide and pyromerylimide,

X denotes a group of the formula --(CH₂)_(n) --, a group of the formula--O(CH₂)_(n) --, a group of the formula --S(CH₂)_(n) --, a group of theformula --NH(CH₂)_(n) --, a group of the formula --SO₂ NH(CH₂)_(n) --, agroup of the formula ##STR14## a group of the formula ##STR15## a groupof the formula ##STR16## a group of the formula --CH₂ NH(CH₂)_(n) --, agroup of the formula ##STR17## (in all the above formulas, n is aninteger of 1 through 7 and R³ represents hydrogen a lower alkyl group ora benzyl group), a group of the formula ##STR18## a group of the formula##STR19## a group of the formula --O--CH₂ CH₂ CH═ or a group of theformula ##STR20##

the ring A denotes a group of the formula ##STR21## a group of theformula ##STR22## a group of the formula ##STR23## or a group of theformula ##STR24## and

R² denotes a hydrogen atom, a lower alkyl group, a substituted orunsubstituted benzyl group, a substituted or unsubstituted benzoylgroup, a pyridyl group, a 2-hydroxyethyl group, a pyridylmethyl group ora group of the formula ##STR25## (wherein Z represents a halogen atom).

The lower alkyl group in the definition of the formula (I) means astraight-chain or branched alkyl group having 1 to 6 carbon atoms, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl or n-hexyl.Preferable lower alkyl groups include a methyl group, ethyl group, etc.The lower alkoxy group means a group derived from the above lower alkylgroup.

The univalent group derived from substituted or unsubstituted benzene inthe definition of R¹ means specifically the following:

(1) Univalent group of the formula ##STR26## wherein n is an integer of1 through 3 and D denotes a substituent substituted by a group or two orthree of the same or different substituent groups selected from thegroup consisting of a hydrogen atom, a lower alkyl group, a nitro group,a lower alkoxy group, an alkylenedioxy group formed between adjacentcarbon atoms in arbitrary positions, a cyano group, a halogen atom, anamino group, a monoalkylamino or dialkylamino group, a loweralkoxycarbonyl group, a trifluoromethyl group, a formyl group, a hydroxygroup (hydroxyl group), a lower alkylthio group, a lower alkylsulfinylgroup, a lower alkylsulfonyl group, a lower alkylsulfoxide group, alower alkylcarbonyl group, a methoxymethylthio group, ahalogenomethylthio group, a cycloalkylsulfonyl group, a phenyl group,phenoxy, a cycloalkylthio group and a cyclohexenyloxy group.

(2) Univalent group of the formula ##STR27## wherein G denotes a groupof the formula ##STR28## a group of the formula ##STR29## a group of theformula --O--, a group of the formula ##STR30## a group of the formula--CH₂ --O--, a group of the formula --CH₂ --SO₂ --, a group of theformula ##STR31## or a group of the formula ##STR32## E denotes a carbonatom or a nitrogen atom, and D has the same meaning as defined in (I).

In the univalent group derived from substituted or unsubstitutedphthalimide in the definition of R¹, the examples of the preferablesubstituent include a nitro group, an amino group, a halogen group, alower alkyl group, a lower alkoxy group, a hydroxy group, a benzoylgroup, a phenylcarbonyl group, a phenylcarbonylamino group, a loweralkylcarbonylamino group, a hydroxycarbonyl group, a benzylaminocarbonylgroup and a dialkylaminocarbonyl group. The univalent group may besubstituted by two or more same or different substituents if necessary.

In the univalent group derived from substituted or unsubstitutedquinazolinedione in the definition of R¹, the examples of the preferablesubstituent include a lower alkyl group and a halogen group.

Preparation Method A ##STR33## wherein Hal denotes a halogen atom, andR¹, X, R² and the ring A have the same meaning as defined above.

Namely, a compound of the general formula (II) (wherein Hal denotes achlorine atom, bromine atom, iodine atom, etc. and among them thebromine atom is most preferable) and a piperidine derivative of thegeneral formula (III) are subjected to a condensation reaction by aconventional method, preferably in the presence of a base such as sodiumhydrogencarbonate, sodium carbonate, potassium carbonate ortriethylamine, to obtain the final compound (I). In this case, as anorganic solvent there is used, for example, benzene, toluene, ethanol,butanol or dimethylformamide (DMF).

Preparation Method B

[In the case where X denotes a group of the formula ##STR34## in thegeneral formula (I)] ##STR35##

Namely, an acid halogenide of the general formula (IV) is allowed toreact with a piperidine derivative of the general formula (V) in anorganic solvent such as chloroform, benzene, toluene, dioxane,tetrahydrofuran or dimethylformamide (DMF), in the presence of adesalting agent such as sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide or triethylamine, with ice-cooling, atroom temperature or with heating, to easily obtain the compound (VI),one of the final compounds.

Preparation Method C

[In the case where X denotes a group of the formula --SO₂ --NH(CH₂)_(n)-- in the general formula (I)] ##STR36##

Procedure similar to that of Preparation Method B is used to obtain thecompound (IX), one of the final compounds.

Preparation Method D

[In the case where R¹ denotes a univalent group derived from imideselected among substituted phthalimide, homophthalimide,pyridinecarboxylic acid imide, pyrazinedicarboxylic acid imide,naphthalenedicarboxylic acid imide, 1,8-naphthalimide,bicyclo[2.2.2]octo-5-ene-2,3-dicarboxylic acid imide and pyromerylimideand X denotes a lover alkylene group in the general formula (I)]##STR37## wherein n is an integer of 1 through 7 and B denotes a residueafter the removal of a group of the formula ##STR38## in all theabove-defined R¹.

Namely, an acid anhydride of the general formula (X) and a piperidinederivative of the general formula (XI) are subjected to a condensationreaction by a conventional method to obtain the compound (XII), one ofthe object substances.

The reaction is carried out with application of heat in an organicsolvent such as, for example, ethanol, butanol, dioxane,dimethylformamide (DMF) or acetic anhydride.

Preparation Method E

[In the case where R¹ denotes a univalent group derived from substitutedquinazolinedione and X denotes a lower alkylene group] ##STR39##

R⁵ and R⁶ are hydrogen, or a substituent such as a lower alkyl and ahalogen.

Namely, a diester of the general formula (XIII) is allowed to react witha piperidine derivative of the general formula (XIV), with applicationof heat, in a suitable solvent which does not participate in thereaction or in the absence of tho solvent to obtain the quinazolonecompound (XV), one of the object substances.

Preparation Method F

[In the case where R¹ denotes a univalent group derived from substitutedor unsubstituted benzene and X denotes a group of the formula--O(CH₂)_(n) -- in the general formula (I)] ##STR40##

R⁷ is hydrogen or a phenyl defined above. p is zero or an integer of 1to 3.

Namely, a phenol derivative of the general formula (XVI) and a halogencompound of the general formula (XVII) are subjected to a condensationreaction by a conventional method to obtain the compound (XVIII), one ofthe final compounds.

The reaction is carried out in a solvent such as, for example,tetrahydrofuran or dimethylformamide (DMF), in the presence of NaH orNaOH, at room temperature or with heating, thereby obtaining a goodresult.

Preparation Method G

[In the case where R¹ denotes a univalent group derived from substitutedor unsubstituted benzene and X denotes a group of the formula--S(CH₂)_(n) -- in the general formula (I)] ##STR41##

Procedure similar to that of Preparation Method F is used to obtain thecompound (XXI), one of the object substances.

Preparation Method H ##STR42## wherein R¹, X, R² and the ring A have thesame meaning as defined above.

Namely, a compound of the general formula (XXII) and a piperidinederivative of the general formula (III) are subjected to a condensationreaction preferably using a desalting agent such as triethylamine,N-methylmorpholine or N,N'-dimethylaniline to obtain the objectsubstance (I).

In this case, benzene, toluene, tetrahydrofuran, dimethylformamide ordioxane is used as a solvent.

Various attempts have been made to treat for middle-age dementia, seniledementia and so on with medicines. At present, however, there is nomedicine which is considered to be drastically effective for thediseases. Considered to be effective at present are anticholinesteraseagents (example; physostygumine). The physostygumine, however, suffersdisadvantages: action of short duration, strong side effects, and soforth.

Accordingly, the inventors have been making many intensive studies overa long term of years in order to develop medicines having actions oflong duration and being high in safety.

As a result, they have discovered that the piperidine derivatives of thegeneral formula (I) can attain the desired end.

Specifically, the compounds of the structural formula (I) according tothe invention have the following important features. They have strongand highly-selective antiacetylcholinesterase activities. Furthermore,they increase the amount of acetylcholine in the brain and are effectivefor the model of retentive disorder. In addition, they have actions oflong duration and are high in safety, compared with the physostygumineheretofore in use in the field. Thus, the invention is of great value.

Namely, the compounds of the invention are piperidine derivatives of thefollowing general formula (I) or pharmacologically allowable saltsthereof: ##STR43## wherein R¹ denotes a univalent group derived from oneselected among substituted or unsubstituted benzene, pyridine, pyrazine,indole, anthraquinone, quinoline, substituted or unsubstitutedphthalimide, homophthalimide, pyridinecarboxylic acid imide, pyridineN-oxide, pyrazinedicarboxylic acid imide, naphthalenedicarboxylic acidimide, substituted or unsubstituted quinazolinedione, 1,8-naphthalimide,bicyclo [2.2.2]octo-5-ene-2,3-dicarboxylic acid imide andpyromerylimide,

X denotes a group of the formula --(CH₂)_(n) --, a group of the formula--O(CH₂)_(n) --, a group of the formula --S(CH₂)_(n) --, a group of theformula --NH(CH₂)_(n) --, a group of the formula --SO₂ NH(CH₂)_(n) --, agroup of the formula ##STR44## a group of the formula ##STR45## a groupof the formula ##STR46## a group of the formula --CH₂ NH(CH₂)_(n) --, agroup of the formula ##STR47## (in all the above formulas, n is aninteger of 1 through 7 and R³ represents a lower alkyl group or a benzylgroup), a group of the formula ##STR48## a group of the formula##STR49## a group of the formula --O--CH₂ CH₂ CH═ or a group of theformula ##STR50##

the ring A denotes a group of the formula ##STR51## a group of theformula ##STR52## a group of the formula ##STR53## or a group of theformula ##STR54## and

R² denotes a hydrogen atom, a lower alkyl group, a substituted orunsubstituted benzyl group, a substituted or unsubstituted benzoylgroup, a pyridyl group, a 2-hydroxyethyl group, a pyridylmethyl group ora group of the formula ##STR55## (wherein Z represents a halogen atom).

Therefore, the purposes of the invention are to provide a novel compoundwhich is effective for treating various types of dementias and sequelaeof cerebrovascular diseases, methods for preparation of the compound anda pharmaceutical composition comprising the compound as the effectiveingredient.

The pharmacologically acceptable salt to use in the invention includesfor instance an inorganic salt, such as hydrochloride, sulfate,hydrobromate or phosphate, and an organic salt such as formate, acetate,trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonateor toluenesulfonate.

The compound of the invention is effective for the treatment,prevention, remission and improvement of various types of seniledementia, especially senile dementia of the Alzheimer type orAlzheimer's disease, disturbance of attention, aphasia, hypobulia,emotional disorder, memory disorder, hallucinatory-paranoid state andabnormal behavior, accompanying and following cerebrovasular diseasessuch as cerebral apoplexy (cerebral hemorrhage, cerebral infarction),sequelae of encephalitis and cerebral palsy.

Further, the compound of the invention has a strong, highly selectiveanticholinesterase activity and is eventually useful as a medicine basedon that activity.

When the compound is used as the medicine, it may be orally orparenterally administered. It is parenterally administered in the formof an intravenous, hypodermic or intramuscular injection or asuppository. It may be administered also in the form of a sublingualtablet. The dose of the administration depends on conditions of thepatient, such as age, sex, body weight and sensitivity, the method ofthe administration such as times and intervals, properties, preparationand kind of the medicine, kind of effective ingredients, and in caseanother treatment is also effected simultaneously the kind, frequencyand intended effects of the treatment. In general, a dose of theadministration is about 0.1 to 300 mg, preferably about 1 to 100 mg, foran adult. The administration with the amount is made one to four times aday.

When the compounds of the invention are prepared into medicines, theyare prepared into medicines in the form of injections, suppositories,sublingual tablet, tablets, capsules, etc. using ordinary carrier by aconventional method in the technical field of preparation.

In the preparation of injections, pH regulator, buffer, suspendingagent, dissolution adjuvant, stabilizer, preservative, etc. are added tothe principal ingredient when required, and intravenous, hypodermic andintramuscular injections are prepared by a conventional method. In thiscase, the injections may be frozen and dried, if necessary, by aconventional method.

Examples of the suspending agent include methylcellulose, polysorbate80, hydroxyethyl cellulose, gum arabic, tragacanth powder, carboxymethylcellulose sodium, polyoxyethylene sorbitan monolaurate, etc.

Examples of the dissolution adjuvant include polyoxyethylene-hardenedcastor oil, polysorbate 80, amide nicotinate, polyoxyethylene sorbitanmonolaurate, castor oil fatty acid ethyl ester, etc.

Examples of the stabilizer include sodium sulfite, sodium metasulfite,ether, etc. Examples of the preservative include methyl paraoxybenzoate,ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, etc.

The representative compounds of the invention will be describedhereinafter by way of examples. It goes without saying, however, thatthe representative compounds are for purpose of help to theunderstanding of the invention and are not intended as a definition ofthe limits of the invention.

The values of NMR in the following examples are those in freesubstances.

EXAMPLE 1 1-benzyl-4-[γ-(4-nitrophenoxy)propyl]piperidine.hydrochloride##STR56##

0.8 g of p-nitrophenol and 1.4 g ofN-benzyl-4-(γ-bromopropyl)-piperidine are dissolved in 20 ml ofdimethylformamide (DMF). To the mixed solution is added, little bylittle, with stirring at room temperature, 0.3 g of 60% sodium hydride.

Hereafter, the resulting mixture is stirred for 2 hours at roomtemperature and is further stirred for about 6 hours and 30 minutes at70° to 80 ° C. After the solvent is distilled off under reducedpressure, an aqueous chloroform-5% caustic soda solution is added to theresidue followed by shaking sufficiently with a separating funnel toseparate out a chloroform layer.

The chloroform layer is washed with a saturated saline solution, whichis then dried over magnesium sulfate. Chloroform is distilled off underreduced pressure, and the resulting residue is purified using a silicagel column. The distillation is performed using 2% methanol-chloroform.After distilling off the solvent under reduced pressure, the residue isdissolved in ethyl acetate followed by adding a 10% hydrochloricacid-ethyl acetate solution to separate out crystals. Uponrecrystallization from ethanol-water-ethyl ether, 1.9 g (yield: 84.1%)of the titled compound having the following physical properties isobtained.

Melting point (°C.): 229-230.

    ______________________________________                                        Elemental analytical values: C.sub.21 H.sub.26 N.sub.2 O.sub.3.HCl                         C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        64.52       6.96   7.17                                        Found value (%)                                                                              64.21       7.03   7.06                                        ______________________________________                                    

EXAMPLE 2N-[4'-(1'-benzylpiperidine)ethyl]-4-benzylsulfonylbenzamide.hydrochloride##STR57##

3 g of 1-benzyl-4-aminoethylpiperidine and 2.8 g of triethylamine areadded to 100 ml of anhydrous tetrahydrofuran. 4.1 g of4-benzylsulfonylbenzoylchloride is mixed with 50 ml of anhydroustetrahydrofuran with ice-cooling and stirring, which is then addeddropwise to the above mixed solution for about 20 minutes. The resultingmixture is stirred for about 20 minutes at room temperature and isfurther refluxed for about 20 minutes. Then, tetrahydrofuran isdistilled off under reduced pressure. The resulting residue is purifiedusing a column in a similar manner as in Example 1 and is formed into ahydrochloride by a conventional method to obtain 3.55 g of the titledcompound (yield: 49.4%).

Melting point (°C.): 187-188.

    ______________________________________                                        Elemental analytical values: C.sub.28 H.sub.32 N.sub.2 O.sub.3 S.HCl                       C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        65.55       6.48   5.46                                        Found value (%)                                                                              64.64       6.27   5.36                                        3/10 (H.sub.2 O)                                                                             64.86       6.53   5.46                                        ______________________________________                                    

EXAMPLE 3 N-[4'-(1'-benzylpiperidine)ethyl]-4-isonicotinic acidamide.hydrochloride ##STR58## (Preparation Example 1)

2.4 g of isonicotinic acid chloride.hydrochloride is added little bylittle to 4.4 g of 1-benzyl-4-aminoethylpiperidine, 5.6 g of potassiumcarbonate and 50 ml of dioxane while they are cooled with ice andstirred. After the reaction for about 1 hour at room temperature,dioxane is distilled off under reduced pressure. To the resultingresidue are added 50 ml of water and 20 ml of a 5% aqueous NaOH solutionto alkalify the residue. The alkaline residue is then extracted withchloroform. After washing with water, the resulting chloroform layer isdried over potassium carbonate, and chloroform is distilled off underreduced pressure The resulting residue is purified with 2%methanol-chloroform-based and 5% methanol-chloroform-based solvents bythe use of a silica gel column, and is formed into a hydrochloride usinga 10% hydrochloric acid-ethyl acetate solution to obtain 5.1 g of thetitled compound (yield: 70.0%).

(Preparation Example 2)

4.7 g of isonicotinic acid is dissolved in a mixed solution ofdimethylformamide-tetrahydrofuran (1/1). To the mixture are added, at-30° to -15° C., 3.85 g of N-methylformalin and 4.13 g of ethylchlorcarbonate. The resulting mixture is stirred for 5 minutes at -15 °C. Dimethylformamide-tetrahydrofuran solution of 8.33 g ofN-benzylpiperidylethylamine is added to the reaction solution followedby stirring for 2 hours at 0° C. and then 1 hour at room temperature.After removing a precipitate by filtration, the resulting filtrate isconcentrated, and the residue is dissolved in chloroform. After washingwith caustic soda and water, the chloroform layer is dried overmagnesium sulfate, and chloroform is distilled off. The resulting oilyresidue is purified using a silica gel chromato to obtain 9.5 g of thetitled compound (yield: 77.0%).

NMR(δ value, DMSO): 1.14-2.04 (9H, m), 2.8-2.9 (2H, bd), 3.36-3.56 (2H,m), 3.44 (2H, s), 6.2 (1H, bt), 7.24 (5H, s), 7.54 (2H, m), 8.68 (2H,m).

EXAMPLE 4N-methyl-N-[4'-(1'-benzylpiperidine)ethyl]-4-benzylsulfonylbenzamide.hydrochloride##STR59##

5.9 g of 4-benzylsulfonylbenzoylchloride is added little by little to4.6 g of 1-benzyl-4-(N'-methylaminoethyl)piperidine, 5 g oftriethylamine and 40 ml of chloroform while they are cooled with ice andstirred. After the reaction for 12 hours at room temperature, 20 ml ofwater and 20 ml of a 5% aqueous NaOH solution are added to the reactionsolution followed by shaking sufficiently with a separating funnel toseparate out a chloroform layer. After washing with water, thechloroform layer is dried over magnesium sulfate, and chloroform isdistilled off under reduced pressure. The resulting residue is purifiedusing a column in a similar manner as in Example 1 and is formed into ahydrochloride. Upon recrystallization from ethanol, 8.2 g of the titledcompound is obtained (yield: 78.1%).

Melting point (°C.): 200-201.

    ______________________________________                                        Elemental analytical values: C.sub.29 H.sub.34 N.sub.2 O.sub.3 S                           C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        66.08       6.69   5.31                                        Found value (%)                                                                              66.12       6.67   5.21                                        ______________________________________                                    

EXAMPLE 5 N-methyl-N-[4'-(1'-benzylpiperidyl)ethyl]isonicotinic acidamide hydrochloride ##STR60##

3.48 g of N-benzyl-4-(N'-methylaminoethyl)piperidine and 4.6 g ofpotassium carbonate are added to a mixed solution of 40 ml of chloroformand 10 ml of water. To the mixture is added, little by little, withice-cooling and stirring, 3.2 g of isonicotinic acidchloride.hydrochloride.

After stirring for 1 hour at room temperature, 20 ml of water and 10 mlof an aqueous 1N-NaOH solution are added to the reaction solution, and achloroform layer is separated out. After washing with water, thechloroform layer is dried over magnesium sulfate.

Chloroform is distilled off under reduced pressure to obtain 4.3 g of anoily matter. The oily matter is purified using a silica gel column in asimilar manner as in Example 1 and is formed into a hydrochloride.

Upon recrystallization from acetone-ethanol, 4.0 g of the titledcompound is obtained (yield: 72.0%).

    ______________________________________                                        Elemental analytical values: C.sub.21 H.sub.27 N.sub.3 O.2HCl.1/2H.sub.2                   C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        60.14       7.21   10.12                                       Found value (%)                                                                              60.02       7.01   10.16                                       ______________________________________                                    

EXAMPLE 6N-methyl-N-[4'-(1'-benzylpiperidine)ethyl]-4-cyclopentylsulfonylbenzamide.hydrochloride##STR61##

1.1 g of N-benzyl-4-(N'-methylaminoethyl)piperidine and 1.4 g ofpotassium carbonate are added to a mixed solution of 20 ml of chloroformand 5 ml of water. While stirring the mixture at room temperature, asolution in which 1.16 g of 4-cyclopentylsulfonylchloride is dissolvedin 20 ml of chloroform is added dropwise to the mixture. After stirringfor 2 hours at room temperature, 10 ml of water and 5 ml of an aqueous1N-NaOH solution are added to the reaction solution, and a chloroformlayer is separated out. After washing with water, the chloroform layeris dried over magnesium sulfate.

Chloroform is distilled off under reduced pressure to obtain a crudeproduct. The crude product is purified using a silica gel column in asimilar manner as in Example 1 and is formed into a hydrochloride.

Upon recrystallization from ethanol-ether, 1.9 g of the titled compoundis obtained (yield: 80.0%).

Melting point (°C.): 234-236 (decomposition).

    ______________________________________                                        Elemental analytical values: C.sub.27 H.sub.36 N.sub.2 O.sub.3 S.HCl.1/2H.    sub.2 O                                                                                    C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        63.08       7.45   5.45                                        Found value (%)                                                                              63.10       7.25   5.40                                        ______________________________________                                    

EXAMPLE 7N-[2-(N'-benzylpiperidino-4)ethyl]-4-nitrophthalimide.hydrochloride##STR62##

1.0 g of 4-nitro phthalic anhydride and 1.1 g of4-(2-aminoethyl)-benzylpiperidine are added to 30 ml of dioxane. Theresulting mixture is heated and refluxed for 2 hours.

The reaction solution is added with 50 ml of water followed byextracting with chloroform. The resulting chloroform layer is dried overmagnesium sulfate, which is then concentrated to dryness under reducedpressure. The resulting residue is purified with a 5%ethanol-chloroform-based solvent by the use of a silica gel column toobtain 1.3 g of the object substance. The object substance is formedinto a hydrochloride using a 10% hydrochloric acid-ethyl acetatesolution. Upon recrystallization from acetone-isopropyl ether, 0.98 g ofthe titled compound is obtained (yield: 45.1%).

Melting point (°C.): 224-227.

    ______________________________________                                        Elemental analytical values: C.sub.22 H.sub.23 N.sub.3 O.sub.4.HCl                         C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        61.47       5.63    9.77                                       Found value (%)                                                                              61.35       5.69   10.01                                       ______________________________________                                    

EXAMPLE 8 N-[2-(N'-benzylpiperidino-4)ethyl]-2,3-pyrazinedicarboxylicacid imide ##STR63##

7.5 g of 2,3-pyrazinedicarboxylic anhydride and 12.0 g of4-(2-aminoethyl)-benzylpiperidine are stirred for 10 minutes at 120° C.to form a brown tar-like mixture. After allowing to stand for cooling, 7ml of acetic anhydride is added dropwise to the brown tar-like mixtureat 80° C. followed by stirring for about 30 minutes at 100° C. Theresulting tar-like substance is added with and dissolved in 20 ml ofchloroform and is purified using a silica gel column in a similar manneras in Example 1. Since the object substance is not well separated out,the above tar-like substance is further purified by distillation withbenzene and a 10% ethanol-benzene-based solvent, to obtain 5.9 g of theobject compound as a yellow-brown oily matter (yield: 33.6%).

NMR (δ value, DMSO): 1.27-2.02 (9H, m), 2.8-2.9 (2H, bd), 3.46 (2H, s),3.82 (2H, t), 7.26 (5H, s), 8.87 (2H, s).

EXAMPLE 9 N-[2-(N'-benzylpiperidino-4)ethyl]-1,8-naphthalimide ##STR64##

2 g of 1,8-naphthalic anhydride and 2.2 g of 4-(2-aminoethyl)benzylpiperidine are heated and refluxed in a solvent of n-butanol for 6hours.

After allowing to stand for cooling, 50 ml of water is added to thereaction solution followed by extracting with chloroform. The resultingchloroform layer is dried over potassium carbonate, which is thenconcentrated to dryness under reduced pressure.

The oily residue thus obtained is purified with chloroform as adistilling solvent by the use of a silica gel column. The purifiedsubstance is formed into a hydrochloride using a 10% hydrochloricacid-ethanol solution. Upon recrystallization from ethanol-methanol, 2.0g of the object compound is obtained (yield: 46%).

NMR (δ value, DMSO): 2.84 (2H, d), 3.45 (2H, s), 4.4 (2H, q), 7.24 (5H,s), 7.4 (2H, q), 8.1 (2H, dd), 8.5 (2H, dd).

EXAMPLE 103-[2-(1-benzyl-4-piperidino)ethyl]-2,4-(1H,3H)-quinazolidione.hydrochloride##STR65##

A mixture of 50 g of 2-[(ethoxycarbonyl)amino]benzoic acid methyl and 45g of 4-(2-aminoethyl)benzylpiperidine is heated to 190° to 200° C. withstirring, and methanol and ethanol formed are distilled off.

After heating and stirring for about 6 hours, the mixture is purifiedusing a silica gel column in a similar manner as in Example 1 and isformed into a hydrochloride.

Upon recrystallization from ethanol-water, 13.3 g of the titled compoundis obtained (yield: 14.8%).

Melting point (°C.): 208-210.

    ______________________________________                                        Elemental analytical values: C.sub.22 H.sub.25 N.sub.3 O.sub.2.HCl                         C         H      N                                               ______________________________________                                        Theoretical value (%)                                                                        66.07       6.55   10.51                                       Found value (%)                                                                              66.02       6.64   10.75                                       ______________________________________                                    

EXAMPLES 11 TO 137

Compounds prepared using similar procedures as in Examples 1 to 10 areshown in Table 1 and Table 2.

The compounds shown in Tables 1 and 2 are represented by the formula##STR66##

    TABLE 1            Elemental analytical       value (%)      Upper column: Prep-     Melt- Solvent  Theoretical value (%) ara- Ex-  ing for  Bottom column:     tion am-  point recrystalli- Molecular Found value (%) meth- ple R.sup.1 X      A R.sup.2 (°C.) zation formula C HN od                   11      ##STR67##      O(CH.sub.2).sub.3      ##STR68##      ##STR69##      137˜138.5 EtOH-1PC C.sub.20 H.sub.24 H.sub.2 O.sub.3.1/4H.sub.2     O.HCl  62.9862.85 6.74  7.346.65  7.16 A       12     ##STR70##      O(CH.sub.2).sub.3      ##STR71##      H 203˜204 EtOH C.sub.12 H.sub.18 H.sub.2 O.sub.3.HCl  54.4454.38     6.60  9.976.64  9.57 A      13     ##STR72##      O(CH.sub.2).sub.3      ##STR73##      ##STR74##      100˜101 EtOH-1PC C.sub.22 H.sub.25 H.sub.2 O.sub.4  60.7368.50     7.34  7.297.61  7.38 A      14     ##STR75##      O(CH.sub.2).sub.3      ##STR76##      ##STR77##      170˜176 EtOH-1PC C.sub.22 H.sub.27 H.sub.2 O.sub.3 H.HCl     58.0858.01 6.20  6.166.11  6.22 A       15     ##STR78##      O(CH.sub.2).sub.3      ##STR79##      ##STR80##      179˜180 EtOH C.sub.27 H.sub.38 H.sub.2 O.sub.3.HCl  69.4469.51     6.69  6.066.72  6.11 B      16     ##STR81##      O(CH.sub.2).sub.3      ##STR82##      ##STR83##      135˜137 Acetone1PC C.sub.25 H.sub.28 H.sub.2 O.sub.3.HCl     68.2168.01 5.93  5.686.02  5.58 B      17     ##STR84##      OCH.sub.3 CH.sub.3      CH     ##STR85##      ##STR86##      214˜217 EtOH-H.sub.3 O C.sub.21 H.sub.24      H.sub.2 O.sub.3.HCl.1/4H.sub.2 O  64.1264.12 6.53  7.126.58  7.24 B  18      ##STR87##      O(CH.sub.3).sub.7      ##STR88##      ##STR89##      159˜161 EtOH-1PC C.sub.23 H.sub.31 H.sub.2 O.sub.4 F.HCl     62.6862.39 6.75  5.856.69  5.99 A      19     ##STR90##      CONH(CH.sub.2).sub.2      ##STR91##      ##STR92##      107˜113 EtOHEther C.sub.22 H.sub.28 N.sub.2 O.sub.2 S.HCl     62.7762.71 6.94  6.656.91  6.59 B      20     ##STR93##      CONH(CH.sub.2).sub.2      ##STR94##      ##STR95##      186˜188 EtOHEther C.sub.23 H.sub.30 N.sub.2      O.sub.3.HCl  66.2666.15 7.01  6.727.18  6.61 B      21     ##STR96##      CONH(CH.sub.2).sub.2      ##STR97##      ##STR98##      156˜158 -- C.sub.23 H.sub.28 N.sub.2 O.sub.4.HCl  63.8063.74 6.75      6.476.78  6.61 B      22     ##STR99##      CONH(CH.sub.2).sub.2      ##STR100##      ##STR101##      166˜168 -- C.sub.28 H.sub.32 N.sub.2 O.sub.2.HCl (3/5H.sub.2 O)     78.4776.5776.54 7.53  6.547.58  6.247.62  6.38 B      23     ##STR102##      CONH(CH.sub.2).sub.2      ##STR103##      ##STR104##      245˜247(Decom-position) EtOHEther C.sub.24 H.sub.34 H.sub.2     O.sub.3 S.HCl.1/2H.sub.2 O  62.4561.99 7.26  5.607.30  5.68 B  24      ##STR105##      CONH(CH.sub.2).sub.2      ##STR106##      ##STR107##      182˜184 EtOH C.sub.22 H.sub.26 N.sub.2 O.sub.2.HCl  68.2968.33     7.03  7.247.16  7.41 B      25     ##STR108##      CONH(CH.sub.2).sub.2      ##STR109##      ##STR110##      255˜257(Decom-position) EtOH C.sub.27 H.sub.28 N.sub.2      O.sub.3.HCl  71.2371.51 5.98  5.735.80  5.81 B      26     ##STR111##      CONH(CH.sub.2).sub.2      ##STR112##      ##STR113##      225˜226 EtOH C.sub.29 H.sub.33 N.sub.2 O.sub.8.HCl  70.7970.91     6.96  8.547.03  8.61 B      27     ##STR114##      CONH(CH.sub.2).sub.2      ##STR115##      ##STR116##      234˜235 EtOHEther C.sub.22 H.sub.27 N.sub.3 O.HCl  69.4269.31     7.09 10.567.00 10.5610.46 B      28     ##STR117##      ##STR118##      ##STR119##      ##STR120##      183˜184 -- C.sub.22 H.sub.25 N.sub.2 O.HCl  70.8570.87 7.84     7.517.75  7.54 B      29     ##STR121##      ##STR122##      ##STR123##      ##STR124##      174˜175 -- C.sub.12 H.sub.26 N.sub.3 OS.CHl  65.9365.98 7.46      7     6.69.44  6.65 B      30     ##STR125##      ##STR126##      ##STR127##      ##STR128##      164˜165 -- C.sub.24 H.sub.26 N.sub.2 O.sub.3.HCl  69.4769.34 7.58      6.757.53  6.68 B      31     ##STR129##      ##STR130##      ##STR131##      ##STR132##      185˜186 -- C.sub.26 H.sub.34 N.sub.2 O.sub.2.HCl  70.4970.18 7.96      6.327.83  6.54 B      32     ##STR133##      ##STR134##      ##STR135##      ##STR136##      195˜196 -- C.sub.26 HHD 33N.sub.2 O.HCl  74.9074.60 7.41     6.247.46  6.28 B      33     ##STR137##      ##STR138##      ##STR139##      ##STR140##      235˜236 EtOH C.sub.34 H.sub.36 N.sub.2 O.sub.3 .HCl.1/4H.sub.2 O  7     0.3770.12 6.30  5.476.23  5.28 B      34     ##STR141##      CONH(CH.sub.2).sub.2      ##STR142##      ##STR143##      119˜123 EtOH1PC C.sub.26 H.sub.31 N.sub.3 O.sub.2.HCl  63.9163.88 6     .97 11.186.98 11.16      35     ##STR144##      ##STR145##      ##STR146##      ##STR147##      203˜204 -- C.sub.23 H.sub.33 N.sub.2 O.sub.2.HCl  70.0070.00 7.75      6.537.80  6.47 B      36     ##STR148##      CONH(CH.sub.2).sub.3      ##STR149##       CH.sub.3 161˜164 -- C.sub.14 H.sub.21 H.sub.3 O  67.9867.91 8.56     16.998.48 16.76 B      37     ##STR150##      CONH(CH.sub.2).sub.2      ##STR151##      ##STR152##      106˜110 MeOHEther C.sub.28 H.sub.32 N.sub.4 O.sub.2.2HCl     63.5163.35 6.47 10.586.59 10.66 B      38     ##STR153##      CONH(CH.sub.2).sub.2      ##STR154##      ##STR155##      127˜129 MeOH1PC C.sub.28 H.sub.31 N.sub.2      O.sub.2.3HCl  58.0958.18 5.92 12.095.99 11.81 B      39     ##STR156##      CONH(CH.sub.2).sub.2      ##STR157##      ##STR158##      118˜122 Acetone1PC C.sub.27 H.sub.31 N.sub.3 O.sub.8 S.2HCl       6     68.660.88 6.22  7.866.01  7.59 B      40     ##STR159##      ##STR160##      ##STR161##      ##STR162##      135˜136 Acetonen-Hexane C.sub.30 H.sub.36 N.sub.3 O.sub.4 S       6     69.208.89 6.97  5.386.87  5.09 B      41     ##STR163##      ##STR164##      ##STR165##      ##STR166##      176˜178 -- C.sub.29 H.sub.34 N.sub.2 O.sub.4 S  68.7568.66 6.76     5.536.68  5.27 B      42     ##STR167##      ##STR168##      ##STR169##      H 149˜151 MeOH1PC C.sub.22 H.sub.29 N.sub.3 O.sub.3 S  65.9765.92 7     .05  6.996.95  6.90 B      43     ##STR170##      ##STR171##      ##STR172##      ##STR173##      163˜164 EtOH1PC C.sub.27 H.sub.34 N.sub.3 O.sub.4 S  68.7568.46     6.76  5.536.78  5.27      44     ##STR174##      ##STR175##      ##STR176##      CH.sub.2 CH.sub.2 OH 114˜116 MeOH1PC C.sub.30 H.sub.31 N.sub.2     O.sub.3.HCl  69.5569.49 6.23  8.116.33  8.19 B      45     ##STR177##      SO.sub.2      NH(CH.sub.2).sub.3     ##STR178##      ##STR179##      122˜123 EtOH C.sub.26 H.sub.33 N.sub.3 O.sub.4 S  61.6861.57 6.47      7.196.33  7.02 B      46     ##STR180##      --      ##STR181##      ##STR182##      254˜255 EtOH C.sub.20 H.sub.17 N.sub.3 O.sub.4.HCl  59.7059.99     5.02 10.465.13 10.41 C      47     ##STR183##      (CH.sub.2).sub.2      ##STR184##      ##STR185##      177˜179 EtOHEther C.sub.22 H.sub.13 N.sub.3      O.sub.4.HCl  61.4761.59 5.63  9.775.66  9.51 C      48     ##STR186##      (CH.sub.2).sub.2      ##STR187##      ##STR188##      116˜118 MeOH1PC C.sub.23 H.sub.35 N.sub.3 O.sub.4.HCl  61.4761.30 5     .63  9.775.61  9.87 C      49     ##STR189##      (CH.sub.2).sub.2      ##STR190##      ##STR191##      246˜248(Decom-postion) MeOHEther C.sub.14 H.sub.27 N.sub.3     O.sub.3.HCl  69.1168.96 6.00  8.346.12  8.39 C      50     ##STR192##      (CH.sub.2).sub.2      ##STR193##      ##STR194##      238˜239(Decom-position) MeOHEther C.sub.14 H.sub.27 N.sub.3     O.sub.3.HCl  65.2265.43 6.39  9.516.28  9.60 C      51     ##STR195##      (CH.sub.2).sub.2      ##STR196##      ##STR197##      227˜228(Decom-position) EtOHEther C.sub.30 H.sub.31 N.sub.3     O.sub.3.HCl  69.5569.29 6.23  8.116.34  8.08 C      52     ##STR198##      (CH.sub.2).sub.2      ##STR199##      ##STR200##      161˜164 EtOHEther C.sub.27 H.sub.33 N.sub.3      O.sub.3.HCl  66.8066.85 7.27  8.667.05  8.64 C      53     ##STR201##      (CH.sub.2).sub.2      ##STR202##      ##STR203##      162˜163 -- C.sub.27 H.sub.28 N.sub.2 O.sub.3.HCl  71.2270.98 5.98      5.735.96  5.79 C      54     ##STR204##      (CH.sub.2).sub.2      ##STR205##      ##STR206##      221˜222(Decom-position) EtOH1PC C.sub.13 H.sub.26 N.sub.2     O.sub.3.HCl  66.5766.42 6.56  6.756.59  6.67 C      55     ##STR207##      (CH.sub.2).sub. 2      ##STR208##      ##STR209##      221˜224(Decom-position) EtOH1PC C.sub.22 H.sub.24 N.sub.2     O.sub.3.HCl  65.9165.77 6.29  6.996.34  6.69 C      56     ##STR210##      (CH.sub.2).sub.2      ##STR211##      ##STR212##      222˜223(Decom-position) EtOH1PC C.sub.12 H.sub.23 N.sub.2 O.sub.3     Cl.HCl  61.4761.33 5.83  6.245.92  6.31 C      57     ##STR213##      (CH.sub.2).sub.2      ##STR214##      ##STR215##       235˜236(Decom-position) EtOH C.sub.16 H.sub.26 N.sub.2      O.sub.2.HCl  71.8071.49 6.26  6.446.17  6.41 C      58     ##STR216##      (CH.sub.2).sub.2      ##STR217##      ##STR218##      178˜181 Acetone1PC C.sub.21 H.sub.22 N.sub.2 O.sub.3.2HCl     61.7761.46 6.17  6.866.35  7.17 C      59     ##STR219##      (CH.sub.2).sub.2      ##STR220##      ##STR221##      161˜163 Acetone1PC C.sub.21 H.sub.23 N.sub.2 O.sub.5.2HCl     61.7761.51 6.17  6.866.22  7.21 C      60     ##STR222##      (CH.sub.2).sub.2      ##STR223##      ##STR224##      210˜214(Decom-position) EtOH1PC C.sub.13 H.sub.24 N.sub.2     O.sub.3.HCl  69.2568.96 6.82  7.026.80  7.02 C      61     ##STR225##      (CH.sub.2).sub.2      ##STR226##      ##STR227##      266˜268 EtOHMeOH C.sub.14 H.sub.30 N.sub.2      O.sub.5.HCl  69.4769.31 7.53  6.727.46  6.63 C      62     ##STR228##      (CH.sub.2).sub.2      ##STR229##      ##STR230##      198˜204(Decom-position) CHCl.sub.3Ether C.sub.12 H.sub.23 N.sub.3     O.sub.4.HCl  62.2361.94 5.90  9.475.95  9.15 C      63     ##STR231##      (CH.sub.2).sub.3      ##STR232##      ##STR233##      184˜188(Decom-position) EtOHEther C.sub.22 H.sub.23 N.sub.3     O.sub.5.2HCl  60.5560.21 6.24  9.636.11  9.57 C      64     ##STR234##      (CH.sub.2).sub.2      ##STR235##      CH.sub.3 256˜ 258(Decom-position) EtOH1PC C.sub.14 H.sub.19     N.sub.3 O.sub.4.HCl  54.3154.29 5.70 11.005.71 11.01 C      65     ##STR236##      (CH.sub.2).sub.2      ##STR237##      ##STR238##      205˜206 -- C.sub.12 H.sub.13 N.sub.3 O.sub.5.HCl  60.0660.09 5.76      9.145.73  9.08 C      66     ##STR239##      (CH.sub.2).sub.2      ##STR240##      ##STR241##      229231 -- C.sub.18 H.sub.22 N.sub.3 O.sub.4 Cl.HCl  56.9156.91 4.99     9.055.02  9.03 C      67     ##STR242##      CH.sub.2      NH(CH.sub.2).sub.2     ##STR243##      ##STR244##      273˜276(Decom-position) EtOHEther C.sub.21 H.sub.26 N.sub.3.2HCl  6     6.1465.73 7.93  7.79  7.28 A      68     ##STR245##      (CH.sub.2).sub.2      ##STR246##      ##STR247##      212˜213 EtOH C.sub.22 H.sub.24 N.sub.3 O.sub.2 Cl.HCl  60.8360.61 5     .80  9.675.93  9.76 D      69     ##STR248##      (CH.sub.2).sub.2      ##STR249##      ##STR250##      221˜223 EtOHEther C.sub.12 H.sub.27 N.sub.3      O.sub.5.HCl  66.7466.92 6.82 10.156.71 10.04 D

                                      TABLE 2                                     __________________________________________________________________________     ##STR251##                                                                   __________________________________________________________________________     Example                                                                            R.sup.1                           X                                                                                           ##STR252##              __________________________________________________________________________     70                                                                                 ##STR253##                       CONH(CH.sub.2).sub.2                                                                         ##STR254##               71                                                                                 ##STR255##                       CONH(CH.sub.2).sub.2                                                                         ##STR256##               72                                                                                 ##STR257##                       CONH(CH.sub.2).sub.2                                                                         ##STR258##               73                                                                                 ##STR259##                       CONH(CH.sub.2).sub.2                                                                         ##STR260##               74                                                                                 ##STR261##                       CONH(CH.sub.2).sub.2                                                                         ##STR262##               75                                                                                 ##STR263##                       CONH(CH.sub.2).sub.2                                                                         ##STR264##               76                                                                                 ##STR265##                       CONH(CH.sub.2).sub.2                                                                         ##STR266##               77                                                                                 ##STR267##                       CONH(CH.sub.2).sub.2                                                                         ##STR268##               78                                                                                 ##STR269##                       CONH(CH.sub.2).sub.2                                                                         ##STR270##               79                                                                                 ##STR271##                       CONH(CH.sub.2).sub.2                                                                         ##STR272##               80                                                                                 ##STR273##                       CONH(CH.sub.2).sub.2                                                                         ##STR274##               81                                                                                 ##STR275##                       CONH(CH.sub.2).sub.2                                                                         ##STR276##               82                                                                                 ##STR277##                       CONH(CH.sub.2).sub.2                                                                         ##STR278##               83                                                                                 ##STR279##                       CONH(CH.sub.2).sub.2                                                                         ##STR280##               84                                                                                 ##STR281##                       CONH(CH.sub.2).sub.2                                                                         ##STR282##               85                                                                                 ##STR283##                       CONH(CH.sub.2).sub.2                                                                         ##STR284##               86                                                                                 ##STR285##                       CONH(CH.sub.2).sub.2                                                                         ##STR286##               87                                                                                 ##STR287##                       CONH(CH.sub.2).sub.2                                                                         ##STR288##               88                                                                                 ##STR289##                       CONH(CH.sub.2).sub.2                                                                         ##STR290##               89                                                                                 ##STR291##                       CONH(CH.sub.2).sub.2                                                                         ##STR292##               90                                                                                 ##STR293##                       CONH(CH.sub.2).sub.2                                                                         ##STR294##               91                                                                                 ##STR295##                       CONH(CH.sub.2).sub.2                                                                         ##STR296##               92                                                                                 ##STR297##                       CONH(CH.sub.2).sub.2                                                                         ##STR298##               93                                                                                 ##STR299##                       CONH(CH.sub.2).sub.2                                                                         ##STR300##               94                                                                                 ##STR301##                       CONH(CH.sub.2).sub.2                                                                         ##STR302##               95                                                                                 ##STR303##                       CONH(CH.sub.2).sub.2                                                                         ##STR304##               96                                                                                 ##STR305##                       CONH(CH.sub.2).sub.2                                                                         ##STR306##               97                                                                                 ##STR307##                       CONHCH.sub.2 CH                                                                              ##STR308##               98                                                                                 ##STR309##                                                                                                      ##STR310##                                                                                  ##STR311##               99                                                                                 ##STR312##                                                                                                      ##STR313##                                                                                  ##STR314##              100                                                                                 ##STR315##                                                                                                      ##STR316##                                                                                  ##STR317##              101                                                                                 ##STR318##                                                                                                      ##STR319##                                                                                  ##STR320##              102                                                                                 ##STR321##                       CONH(CH.sub.2).sub.3                                                                         ##STR322##              103                                                                                 ##STR323##                       CONH(CH.sub.2).sub.2                                                                         ##STR324##              104                                                                                 ##STR325##                       CONH(CH.sub.2).sub.2                                                                         ##STR326##              105                                                                                 ##STR327##                       CONH(CH.sub.2).sub.2                                                                         ##STR328##              106                                                                                 ##STR329##                       CONH(CH.sub.2).sub.2                                                                         ##STR330##              107                                                                                 ##STR331##                       CH.sub.2                                                                                     ##STR332##              108                                                                                 ##STR333##                       (CH.sub.2).sub.2                                                                             ##STR334##              109                                                                                 ##STR335##                       (CH.sub.2).sub.2                                                                             ##STR336##              110                                                                                 ##STR337##                       (CH.sub.2).sub.2                                                                             ##STR338##              111                                                                                 ##STR339##                       (CH.sub.2).sub.2                                                                             ##STR340##              112                                                                                 ##STR341##                       (CH.sub.2).sub.2                                                                             ##STR342##              113                                                                                 ##STR343##                       (CH.sub.2).sub.2                                                                             ##STR344##              114                                                                                 ##STR345##                       (CH.sub.2).sub.3                                                                             ##STR346##              115                                                                                 ##STR347##                       CONH(CH.sub.2).sub.2                                                                         ##STR348##              116                                                                                 ##STR349##                       CONH(CH.sub.2).sub.2                                                                         ##STR350##              117                                                                                 ##STR351##                       CONH(CH.sub.2).sub.2                                                                         ##STR352##              118                                                                                 ##STR353##                       CONH(CH.sub.2).sub.2                                                                         ##STR354##              119                                                                                 ##STR355##                       CONH(CH.sub.2).sub.2                                                                         ##STR356##              120                                                                                 ##STR357##                       CONH(CH.sub.2).sub.2                                                                         ##STR358##              121                                                                                 ##STR359##                       CONH(CH.sub.2).sub.2                                                                         ##STR360##              122                                                                                 ##STR361##                       CONH(CH.sub.2).sub.2                                                                         ##STR362##              123                                                                                 ##STR363##                       CONH(CH.sub.2).sub.2                                                                         ##STR364##              124                                                                                 ##STR365##                       CONH(CH.sub.2).sub.2                                                                         ##STR366##              125                                                                                 ##STR367##                       CONH(CH.sub.2).sub.2                                                                         ##STR368##              126                                                                                 ##STR369##                       CONH(CH.sub.2).sub.2                                                                         ##STR370##              127                                                                                 ##STR371##                       CONH(CH.sub.2).sub.2                                                                         ##STR372##              128                                                                                 ##STR373##                                                                                                      ##STR374##                                                                                  ##STR375##              129                                                                                 ##STR376##                                                                                                      ##STR377##                                                                                  ##STR378##              130                                                                                 ##STR379##                                                                                                      ##STR380##                                                                                  ##STR381##              131                                                                                 ##STR382##                       CONHCH.sub.2                                                                                 ##STR383##              132                                                                                 ##STR384##                       CONH(CH.sub.2).sub.2                                                                         ##STR385##              133                                                                                 ##STR386##                       (CH.sub.2).sub.2                                                                             ##STR387##              134                                                                                 ##STR388##                                                                                                      ##STR389##                                                                                  ##STR390##              135                                                                                 ##STR391##                                                                                                      ##STR392##                                                                                  ##STR393##              136                                                                                 ##STR394##                                                                                                      ##STR395##                                                                                  ##STR396##              137                                                                                 ##STR397##                                                                                                      ##STR398##                                                                                  ##STR399##              __________________________________________________________________________                      Molecular                              Preparation          Example                                                                            R.sup.2      formula      H.sup.1 -NMR(CDCl.sub.2,                                                                                method               __________________________________________________________________________     70                                                                                 ##STR400##  C.sub.21 H.sub.26 N.sub.2 O.HCl                                                            1.16˜2.04(9H, m), 2.7˜2.96(2H,                                    ), 3.28˜3.56(4H, m), 6.0(1H, s),                                        7.2˜7.76(10H, m)    B                     71                                                                                 ##STR401##  C.sub.31 H.sub.23 N.sub.3 O.sub.3                                                          1.08˜2.12(9H, m), 2.04˜2.96(2H,                                    d), 3.38˜3.6(2H, m), 3.52(2H, s),                                      6.40(1H, bt), 7.3(5H, s), 7.9 (2H, d),                                        8.24(2H, d)               B                     72                                                                                 ##STR402##  C.sub.21 H.sub.25 N.sub.3 O                                                                1.1˜2.06(9H, m), 2.8˜2.9(2H,                                      bd), 3.32˜3.56(4H, s1/2m), 6.36 (1H,                                    t), 7.26(5H, s), 7.64(2H, d), 7.84(2H,                                                                  B)                    73                                                                                 ##STR403##  C.sub.22 H.sub.25 N.sub.2 O.sub.2                                                          1.24˜2.03(9H, m), 2.8˜2.86(2H,                                    ), 3.26˜3.48(2H, m), 3.46(2H, s),                                       3.8(3H, s), 6.14(1H, bt),                                                     6.9˜7.3(9H, m)      B                     74                                                                                 ##STR404##  C.sub.24 H.sub.33 N.sub.2 O.sub.4                                                          1.23˜2.04(9H, m), 2.76˜2.88(2H,                                    bd), 3.35˜3.58(4H, s1/2t), 3.84                                        (9H, s), 6.38(1H, bt), 7.0(2H, s),                                            7.28(5H, s)               B                     75                                                                                 ##STR405##  C.sub.21 H.sub.23 N.sub.2 OCl                                                              2.9(2H, d), 3.45(3H, s, d), 6.26 (1H, bt),                                    7.26(5H, s), 7.3(2H, d), 7.7(2H,                                                                        B)                    76                                                                                 ##STR406##  C.sub.23 H.sub.34 N.sub.2 O.sub.4                                                          2.9(2H, d), 3.46(3H, s, d), 3.78 (6H, s),                                     6.12(1H, bt), 6.5(1H, t), 6.82(2H, d),                                        7.26(5H, s)               B                     77                                                                                 ##STR407##  C.sub.23 H.sub.31 N.sub.3 O                                                                2.7(2H, d), 2.8(6H, s), 3.34(2H, s),                                          6.46(2H, d), 6.5(1H), 7.12 (5H, s),                                           7.59(2H, d)               B                     78                                                                                 ##STR408##  C.sub.23 H.sub. 36 N.sub.2 O.sub.3                                                         1.1˜2.0(9H, m), 2.76˜2.86(2H,                                     bd), 3.26˜3.48(4H, m), 5.94(2H, s),                                     6.32(1H, bt), 6.72(1H, d), 7.24(2H,                                                                     B)                    79                                                                                 ##STR409##  C.sub.23 H.sub.30 N.sub.2 OS                                                               1.02˜2.04(9H, m), 2.8˜2.9(2H,                                     bd), 2.8˜2.9(2H, bd), 3.2˜3.5                                     (4H, s1/2m), 6.26(1H, bt), 7.18(2H, d),                                       7.2H(5H, s), 7.64(2H, d)  B                     80                                                                                 ##STR410##  C.sub.22 H.sub.23 N.sub.2 O.sub.3 S                                                        1.12˜2.06(9H, m), 2.8˜2.9(2H,                                     bd), 3.04(3H, s), 3.36˜3.58(2H, m),                                     3.48(2H, s), 6.3(1H, bt), 7.26 (5H, s),                                       7.9(4H, s)                B                     81                                                                                 ##STR411##  C.sub.22 H.sub.23 N.sub.2 OP.sub.3                                                         1.3˜2.08(9H, m), 2.86(2H, bd),                                          3.46(2H, s), 6.0(1H, bs), 7.16(5H, s),                                        7.64(2H, d), 7.82(2H, d)  B                     82                                                                                 ##STR412##  C.sub.22 H.sub.26 N.sub.2 O.sub.2                                                          1.2˜2.20(9H, m), 2.98(2H, bd),                                          3.42(3H, m), 3.60(2H, s), 7.30(5H, s),                                        7.92(4H, s), 10.02(1H, s) B                     83                                                                                 ##STR413##  C.sub.21 H.sub.26 N.sub.2 O.sub.2                                                          1.2˜2.04(9H, m), 2.84(2H, bd),                                          3.30(2H, m), 3.46(2H, s), 6.52(1H, bs),                                       6.66(2H, d), 7.22(5H, s), 7.52(2H, d),                                        8.30(1H, s)               B                     84                                                                                 ##STR414##  C.sub.24 H.sub.32 N.sub.2 O.sub.2                                                          1.1˜2.04(9H, m), 2.04(2H, bd),                                          3.44(4H, s1/2m), 5.06(2H, m), 6.00 (1H,                                       bt), 6.92(2H, d), 7.14˜7.44 (10H,                                       m), 7.68(2H, d)           B                     85                                                                                 ##STR415##  C.sub.21 H.sub.33 N.sub.3 O.sub.2                                                          1.06˜2.04(15H, m), 2.8(2H, bd),                                         3.10˜3.60(8H, s1/2m), 6.96(1H, bt),                                     7.22(7H, s1/2d), 7.66(2H,                                                                               B)                    86                                                                                 ##STR416##  C.sub.27 H.sub.34 N.sub.2 O.sub.2                                                          1.1˜2.1(15H, m), 2.76˜2.88(2H,                                    d), 3.3˜3.5(2H, m), 3.44(2H, s),                                        4.8(1H, m), 5.7˜6.04(2H, m), 6.88                                       (2H, d), 7.28(5H, m), 7.64(2H,                                                                          B)                    87                                                                                 ##STR417##  C.sub.23 H.sub.27 N.sub.3 O.sub.2                                                          1.3˜2.0(7H, m), 2.7˜3.4(6H,                                       m), 4.14˜4.36(5H, m),                                                   7.3˜8.04(9H, m), 8.40(1H, m),                                           10.00(1H, m)              B                     88                                                                                 ##STR418##  C.sub.28 H.sub.31 N.sub.2 OS                                                               1.0˜1.9H(9H, m), 2.6˜2.86(2H,                                     m), 3.08˜3.5( , m1/2s), 4.28(2H, s),                                    7.2˜7.4(12H, m), 7.7(2H, d),                                            8.32(1H, bt)              B                     89                                                                                 ##STR419##  C.sub.26 H.sub.34 N.sub.2 OS                                                               1.2˜2.3(17H, m), 3.08˜3.2(2H,                                     bd), 2.5˜2.78(5H, m), 3.1(1H, m),                                       7.06˜7.9(9H, m)     B                     90                                                                                 ##STR420##  C.sub.27 H.sub.30 N.sub.2 O.sub.2                                                          1.24˜2.04(9H, m), 2.76˜2.88(2H,                                    bd), 3.3˜3.5(6H, s1/2m), 6.1(1H,                                       bt), 6.88˜7.74(14H,                                                                               B)                    91                                                                                 ##STR421##  C.sub.23 H.sub.30 N.sub.2 O.sub.2 S                                                        1.22˜2.06(9H, m), 2.8˜2.92(2H,                                    bd), 3.38(3H, s), 3.44(2H, s),                                                3.28-3.44(2H, m), 4.94(2H, s), 6.36(1H,                                       bt), 7.26(5H, s), 7.4(2H, d), 7.64(2H,                                                                  B)                    92                                                                                 ##STR422##  C.sub.27 H.sub.31 N.sub.3 O.sub.2                                                          1.24˜2.06(9H, m), 2.88(2H, bd),                                         3.40(2H, t), 3.48(2H, s), 5.11(2H, s),                                        5.94(1H, bs), 6.94(2H, d), 7.28(5H, s),                                       7.32(2H, d), 7.7(2H, d), 8.6(2H,                                                                        B)                    93                                                                                 ##STR423##  C.sub.26 H.sub.23 N.sub.3 O                                                                2.9(2H, d), 3.48(3H, s, d), 6.7(1H, ht),                                      7.28(6H, s), 7.1(1H, ), 7.65 (1H, ),                                          7.9(1H, )                 B                     94                                                                                 ##STR424##  C.sub.26 H.sub.24 N.sub.3 OCl                                                              1.26˜2.05(9H, m), 2.8˜2.9(2H,                                     bd), 3.32˜3.54(4H, s1/2m), 6.56 (1H,                                    ht), 7.28(5H, s), 7.34(1H, d), 8.02(1H,                                       dd), 8.7(1H, d)           B                     95                                                                                 ##STR425##  C.sub.17 H.sub.24 N.sub.4 O                                                                1.3˜2.07(9H, m), 2.8˜2.92(2H,                                     bd), 2.38˜2.6(4H, s1/2m), 7.27 (5H,                                     s), 7.7(1H, ht), 8.5(1H, d), 8.7(1H, d),                                      9.38(1H, d)               B                     96                                                                                 ##STR426##  C.sub.24 H.sub.26 N.sub.3 O                                                                2.86(2H, d), 3.48(4H, s, d), 6.44 (1H,                                        1b), 7.26(5H, s), 7.4˜7.8 (3H),                                         8.4(2H), 8.74(1H, d)      B                     97                                                                                 ##STR427##  C.sub.30 H.sub.23 N.sub.3 O                                                                2.24˜2.56(8H, m), 3.56(2H, s),                                          4.0(2H, t), 5.28(1H, t), 6.64(1H, bs),                                        7.31(5H, s), 7.6(2H, dd), 8.66(2H,                                                                      Bd)                   98                                                                                 ##STR428##  C.sub.27 H.sub.31 N.sub.2 O.sub.2.HCl                                                      0.8˜2.10(11H, m), 2.49˜2.88                                       (7H, m), 7.04˜7.84(14H,                                                                           B)                    99                                                                                 ##STR429##  C.sub.22 H.sub.30 N.sub.2 O.sub.3 S.HCl                                                    0.92˜2.10(9H, m), 2.44˜3.6(7H,                                    ), 3.0(3H, s), 3.44(2H, bd), 7.14 (5H, s),                                    7.52(2H, d), 7.96(2H, d)  B                    100                                                                                 ##STR430##  C.sub.22 H.sub.27 N.sub.3 O                                                                1.02˜2.10(12H, m), 2.7˜3.7(8H,                                    ), 8.2˜8.28(7H, d, s), 8.68(2H,                                                                   B)                   101                                                                                 ##STR431##  C.sub.27 H.sub.31 N.sub.3 O                                                                1.04˜2.04(9H, m), 2.7˜3.7(6H,                                     m), 4.4(2H, s), 4.74(2H, s),                                                  7.00 ˜7.6(12H, m), 8.64(2H,                                                                       Bs)                  102                                                                                 ##STR432##  C.sub.21 H.sub.27 N.sub.3 O                                                                1.14˜2.04(11H, m), 2.78˜2.9(2H                                    d), 3.16˜3.76(4H, s, d), 6.5 (1H,                                       s), 7.26(5H, s), 7.56(2H, d), 8.68(2H,                                                                  B)                   103                                                                                 ##STR433##  C.sub.17 H.sub.24 N.sub.4 O                                                                1.3˜2.1(9H, m), 2.76˜2.88(2H,                                     m), 3.16˜3.58(4H, m, s), 6.84(1H,                                       s), 7.24(2H, d), 7.6(2H, d), 8.48 (2H, d),                                    8.68(2H, d)               B                    104                                                                                 ##STR434##  C.sub.20 H.sub.23 N.sub.3 O.sub.2 Cl.sub.2                                                 2.8(2H, d), 3.4(4H, s, t), 7.5˜                                         7.1(3H), 7.62(2H), 8.64(2H)                                                                             B                    105                                                                                 ##STR435##  C.sub.18 H.sub.22 N.sub.4 O                                                                1.22˜1.96(7H, m), 2.7˜3.0(2H,                                     m), 3.4˜3.62(2H, m), 3.8˜3.85                                     (2H, m), 6.62(3H, m, s), 7.58(2H, d),                                         8.7(2H, d)                B                    106                                                                                 ##STR436##  C.sub.21 H.sub.27 N.sub.3 O.sub.2                                                          1.04˜2.16(9H, m), 2.82(2H, d),                                          3.32˜3.62(2H, m), 3.46(2H, s),                                          6.32˜6.58(1H, m), 7.16˜8.56(13H                                   , m)                      B                    107                                                                                 ##STR437##  C.sub.21 H.sub.21 N.sub.3 O.sub.4                                                          1.26˜2.06(9H, m), 2.78˜2.9(2H,                                    d), 3.45(2H, s), 3.62(2H, d), 7.24(5H, s),                                    7.95˜8.04(1H, m), 8.5˜8.6(2H,                                     m)                        C                    108                                                                                 ##STR438##  C.sub.22 H.sub.24 N.sub.3 O.sub.2                                                          1.26˜2.04(9H, m), 2.84(2H, bd),                                         3.44(2H, s), 3.68(2H, t), 7.24 (5H, s),                                       7.7(4H, m)                C                    109                                                                                 ##STR439##  C.sub.23 H.sub.25 N.sub.3 O.sub.2                                                          1.28˜2.04(9H, m), 2.85(2H, bd),                                         3.46(2H, s), 3.62(2H, t), 5.17 (2H, s),                                       6.78(1H, d), 7.1(1H, d), 7.25(5H, s),                                         7.36(1H, t)               C                    110                                                                                 ##STR440##  C.sub.22 H.sub.25 N.sub.3 O.sub.2                                                          1.26˜2.04(9H, m), 2.84(2H, bd),                                         3.48(2H, s), 3.6(2H, t), 5.31 (2H, s),                                        6.76(1H, dd), 6.98(1H, d), 7.27(5H, s),                                       7.54(1H, d)               C                    111                                                                                 ##STR441##  C.sub.27 H.sub.27 N.sub.3 O.sub.3                                                          1.28˜2.06(9H, m), 2.86(2H, bd),                                         3.50(2H, s), 3.68(2H, t), 7.28 (5H, s),                                       7.50(3H, m), 7.86(3H, m), 8.1(2H, m),                                         8.36(1H, s)               C                    112                                                                                 ##STR442##  C.sub.20 H.sub.43 N.sub.4 O.sub.4                                                          2.84(2H, d), 2.44(2H, s), 2.7 (2H, t),                                        7.24(10H, s), 8.2(2H, s)  C                    113                                                                                 ##STR443##  C.sub.23 H.sub.27 N.sub.3 O.sub.2                                                          1.0˜2.2(8H, m), 2.41(3H, s),                                            2.7˜3.1(2H, m), 3.5(2H, s), 4.11(2H,                                    t), 7.8˜8.9(8H, m)  D                    114                                                                                 ##STR444##  C.sub.23 H.sub.27 N.sub.3 O.sub.2                                                          0.9˜2.2(8H, m), 2.7˜3.0(2H,                                       m), 3.48(2H, s), 4.06(2H, t),                                                 7.9˜8.7(8H, m), 8.0˜8.2(1H,                                                                 D)                   115                                                                                 ##STR445##  C.sub.23 H.sub.27 N.sub.2 OSCl.HCl.1/3H.sub.2 O                                            0.92˜2.04(9H, m), 2.64˜3.00(2H,                                    bd), 3.12 ˜3.60(2H, m), 3.40(2H,                                       s), 4.96(2H, s), 6.48 ˜6.76(1H, bt),                                    7.08˜7.84(9H, m)    B                    116                                                                                 ##STR446##  C.sub.23 H.sub.32 N.sub.2 O.sub.2 S.HCl.3/2H.sub.2                                         1.0˜2.10(9H, m), 2.70˜2.96(2H,                                    bd), 3.20 ˜3.60(2H, m), 3.46(2H, s),                                    4.00(2H, d), 6.20 (1H, bs),                                                   6.84˜7.80(14H, m)   B                    117                                                                                 ##STR447##  C.sub.24 H.sub.23 N.sub.2 O.HCl                                                            1.20(3H, s), 1.28(3H, s),                                                     1.00˜2.08(9H, m),  2.64˜3.02(3H                                   , m), 3.45(2H, s), 3.24˜3.56 (2H,                                       m), 6.36(1H, bt), 7.12˜7.76(9H,                                                                   B)                   118                                                                                 ##STR448##  C.sub.22 H.sub.35 N.sub.3 O.sub.2.HCl                                                      1.00˜3.08(14H, m),                                                      2.64˜2.96(2H, bd), 3.44(2H, s),                                         3.32˜3.48(2H, m), 3.80(3H, s),                                          6.76˜7.52(9H, m)    B                    119                                                                                 ##STR449##  C.sub.23 H.sub.23 N.sub.3 O.sub.2.HCl                                                      1.00˜3.08(14H, m), 2.60(3H, s),                                         3.24˜3.62 (2H, bd), 3.46(2H, s),                                        6.16(1H, bt), 7.26(5H, s),                                                    7.08˜8.00(4H, bd)   B                    120                                                                                 ##STR450##  C.sub.22 H.sub.33 N.sub.2 O.HCl                                                            1.04˜2.12(14H, m), 2.36(3H, s),                                         2.68˜2.96 (2H, bd),                                                     3.28˜3.56(2H, m), 3.44(2H, s),                                          6.00(1H, bt), 7.08˜7.70(9H,                                                                       B)                   121                                                                                 ##STR451##  C.sub.23 H.sub.34 N.sub.2 O.sub.3.HCl                                                      1.10˜2.08(14H, m),                                                      2.68˜2.98(2H, bd), 3.28˜3.56(2H                                   , m), 3.46(2H, s), 3.08(3H, s), 3.89(3H,                                      s), 5.94(1H, bt), 6.72˜8.44(8H,                                                                   B)                   122                                                                                 ##STR452##  C.sub.22 H.sub.34 N.sub.2 O.sub.2.HCl                                                       0.72˜2.48(9H, m),                                                      2.48˜3.00(2H, bd), 3.48 (2Hs),                                          3.20˜3.60(2H, m), 6.40˜6.60(1H,                                    bt), 7.08˜7.92(14H,                                                                              B)                   123                                                                                 ##STR453##  C.sub.27 H.sub.30 N.sub.2 O.HCl                                                            1.12˜3.12(9H, m), 2.68˜3.00(2H,                                    bd), 3.32 ˜3.62(2H, m), 3.46(2H,                                       s), 6.06(1H, bt), 7.12˜7.88(14H,                                                                  B)                   124                                                                                 ##STR454##  C.sub.22 H.sub.30 N.sub.2 O.sub.3.HCl                                                      0.92˜3.08(14H, m),                                                      2.64˜2.98(2H, bd), 3.45(2H, s),                                         3.24˜3.60(2H, m), 6.24(1H, bt),                                         7.04˜8.28(14H, m)   B                    125                                                                                 ##STR455##  C.sub.23 H.sub.23 N.sub.2 O.HCl                                                            0.96˜2.08(14H, m),                                                      2.68˜2.96(2H, bd), 3.44(2H, s),                                         3.28˜3.62(2H, m), 3.26(1H, bt),                                         7.08˜8.28(12H, m)   B                    126                                                                                 ##STR456##  C.sub.24 H.sub.25 N.sub.2 O.HCl                                                            1.2˜2.06(7H, m), 2.80˜2.92(2H,                                    bd), 3.33 ˜3.6(2H), 3.46(2H, s),                                        7.27(5H, s), 7.3˜8.54(5H,                                                                         B)                   127                                                                                 ##STR457##  C.sub.21 H.sub.22 N.sub.2 OH.HCl                                                           1.04˜2.10(14H, m),                                                      2.68˜2.38(2H, bd), 3.46(2H, s),                                         3.24˜3.56(2H, m), 6.06(1H, bt),                                         6.88˜7.04(9H, m)    B                    128                                                                                 ##STR458##  C.sub.23 H.sub.30 N.sub.2 O.sub.2.HCl                                                      0.96˜3.08(14H, m),                                                      2.60˜3.03(2H, bd), 2.97(3H, s),                                         3.03˜3.60(2H, m), 3.45(3H, S),                                          3.79(3H, s), 6.72˜7.40(9H,                                                                        B)                   129                                                                                 ##STR459##  C.sub.27 H.sub.34 N.sub.2 O.sub.2.HCl.1/2H.sub.2                                           1.04˜2.04(9H, m), 2.80(2H, broad d),                                    2.98 (3H, d) 3.20˜3.48(2H, m),                                          3.24(2H, s), 5.06(2H, s), 6.90(2H, d),                                        7.16˜7.44(12H, m)   B                    130                                                                                 ##STR460##  C.sub.36 H.sub.31 N.sub.2 O.sub.3 S.HCl.1/2H.sub.2                                         0.92˜1.96(12H, m),                                                      2.60˜3.54(8H, m), 4.36(2H, s),                                          6.96˜7.44(12H, m), 7.60(2H,                                                                       B)                   131                                                                                 ##STR461##  C.sub.12 H.sub.23 N.sub.3 O                                                                1.2˜2.08(7H, m), 2.82˜2.95(2H,                                    bd), 3.27˜3.4(2H, t), 3.48(2H, s),                                      6.4(1H), 7.26(5H, s), 7.53˜7.60(2H),                                    8.65˜8.73(2H)       B                    132                                                                                 ##STR462##  C.sub.27 H.sub.27 N.sub.3 O.sub.2.2HCl                                                     1.04˜2.20(14H, m),                                                      2.64˜2.95(2H, bd), 3.32˜3.64(2H                                   , m), 3.46(2H, s), 6.48(1H, bt),                                              7.12˜8.56(13H, m)   B                    133                                                                                 ##STR463##  C.sub.22 H.sub.23 N.sub.2 O.sub.2 Cl                                                       1.07˜2.50(9H, m), 2.71˜2.82(2H,                                    bd), 3.36(2H, s), 3.5˜3.67(2H, t),                                     7.16(5H, s), 7.46˜7.76(3H,                                                                        C)                   134                                                                                 ##STR464##  C.sub.22 H.sub.27 N.sub.3 O.sub.3                                                          1.05˜2.05(9H, m), 2.80˜3.1(5H,                                    m), 3.50(2H, d), 7.35(5H, s), 7.60(2H, d),                                    8.30(2H, d),              B                    135                                                                                 ##STR465##  C.sub.23 H.sub.29 N.sub.3 O.sub.3                                                          1.05˜2.0(9H, m), 3.2(2H, d),                                            3.45(2H, d), 7.30(5H, s), 7.50(2H,                                                                      B),                  136                                                                                 ##STR466##  C.sub.22 H.sub.27 N.sub.3 O                                                                1.0˜2.0(9H, m), 2.65˜3.05,                                        (5H, m), 3.45(2H, s), 7.30(5H, s),                                            7.45(2H, d), 7.70(2H, d), 8.30(2H,                                                                      B),                  137                                                                                 ##STR467##  C.sub.23 H.sub.29 N.sub.3 O                                                                1.0˜2.0(9H, m), 2.8(2H, d), 3.15(2H,                                    d), 3.45(2H, s), 7.30(5H, s), 7.35(2H, d),                                    7.60(2H, d),              B                    __________________________________________________________________________

In order to show the effects of the compounds of the invention indetail, part of examples of pharmacological experiments using animalswill be described hereinunder.

In addition to the working examples disclosed above in view of thepharmacological tests, the compound of the invention was examined inview of effects on scopolamine-induced impairment of passive avoidance,using ddY male mice. As a result it was found that it had an excellentactivity in this respect.

EXPERIMENTAL EXAMPLE 1 Acetylcholinesterase Inhibitory Action usingMouse Brain Homogenate

Using a mouse brain homogenate as a source of acetylcholinesterase, theesterase activity was measured by a thiocholine method. Acetylcholine asa substrate, the compound of the invention as a substance to test and5,5'-dithio-bis(2-nitrobenzoic acid), called also DTNB, were added tothe mouse brain homogenate. After incubation, thiocholine produced wasreacted with DTNB to form a yellow product. The acetylcholinesteraseactivity was determined by the measurement of the absorbance change ofthe reaction product at 412 nm.

The acetylcholinesterase inhibitory activity of the compound tested wasexpressed in terms of the 50% inhibitory concentration, IC50.

Results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                       AchE inhibitory                                                Compound       activity                                                       (Example No.)  IC.sub.50 (μM)                                              ______________________________________                                        4              0.0006                                                         5              0.088                                                          6              0.021                                                          7              0.014                                                          8              0.08                                                           9              0.0055                                                         10             0.0042                                                         16             0.059                                                          21             0.021                                                          25             0.0045                                                         26             0.009                                                          32             0.0043                                                         41             0.0008                                                         47             0.009                                                          48             0.0039                                                         50             0.0028                                                         51             0.0022                                                         52             0.0015                                                         53             0.0024                                                         54             0.008                                                          56             0.0033                                                         57             0.0012                                                         58             0.013                                                          62             0.0034                                                         68             0.045                                                          71             0.055                                                          88             0.049                                                          98             0.0083                                                         110            0.0088                                                         111            0.00088                                                        112            0.00015                                                        113            0.0047                                                         115            0.0067                                                         116            0.009                                                          122            0.02                                                           123            0.0105                                                         130            0.0003                                                         133            0.0079                                                         Physo *1       0.89                                                           THA *2         0.084                                                          ______________________________________                                         (Notes)                                                                       *1; physostigmine                                                             *2; 1,2,3,4Tetrahydro-9-Aminoacridine                                    

EXPERIMENTAL EXAMPLE 2 Acute Toxicity Test for ddY Male Mouse

Acute toxicity test was carried out using ddY male mice.

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Compound       Oral to mouse (mg/kg)                                          (Example No.)  100 mg    300 mg                                               ______________________________________                                        4                0/3 *1    2/4 *1                                             5              1/4       4/4                                                  7              --        0/3                                                  10             3/4       --                                                   ______________________________________                                         (Notes)                                                                       *1; Denominator shows the number of Animals used, and numerator shows the     number of deaths.                                                        

What is claimed is:
 1. A piperidine derivative having the formula (I) ora pharmacologically acceptable salt thereof: ##STR468## wherein R¹ isanthraquinone, X is --(CH₂)_(n) --, --O(CH₂)_(n) --, --S(CH₂)_(n) --,--NH(CH₂)_(n) --, --SO₂ NH(CH₂)_(n) --, ##STR469## wherein n is aninteger of 1 through 7 and R³ is hydrogen, lower alkyl or benzyl,##STR470## and R² is hydrogen, lower alkyl, benzyl, benzyl substitutedwith hydroxy, methoxy or chlorine, benzoyl, benzoyl with a fluorinesubstituent, pyridyl, 2-hydroxyethyl, pyridylmethyl or a group of theformula ##STR471## wherein Z represents a halogen atom.
 2. A piperidinederivative having the formula (I) or a pharmacologically acceptable saltthereof: ##STR472## wherein R¹ is anthraquinone, X is --(CH₂)_(n) --,--O(CH₂)_(n) --, --S(CH₂)_(n) --, --NH(CH₂)_(n) --, --SO₂ NH(CH₂)_(n)--, ##STR473## --CH₂ NH(CH₂)_(n) --, wherein n is an integer of 1through 7 and R³ is hydrogen, lower alkyl or benzyl, ##STR474## and R²is hydrogen, lower alkyl, benzyl, benzyl substituted with hydroxy,methoxy or chlorine, benzoyl, benzoyl with a fluorine substituent,pyridyl, 2-hydroxyethyl, pyridylmethyl or ##STR475## wherein Zrepresents a halogen atom.
 3. A piperidine derivative or apharmacologically acceptable salt as claimed in claim 1, in which X is agroup of the formula: ##STR476## n is an integer of 1 through 7 and R³represents a lower alkyl group or a benzyl group.
 4. A piperidinederivative or a pharmacologically acceptable salt as claimed in claim 1,in which X is a group of the formula: ##STR477## n is an integer of 1through 7 and R³ represents a lower alkyl group or a benzyl group, andthe ring A is a group of the formula ##STR478##
 5. A piperidinederivative or a pharmacologically acceptable salt as claimed in claim 1,in which X is a group of the formula: ##STR479## wherein n is a integerof 1 through 7 and R³ represents a lower alkyl group or a benzyl group,the ring A is a group of the formula ##STR480## and R² is benzyl orbenzyl substituted with hydroxy, methoxy or chlorine.
 6. A piperidinederivative or a pharmacologically acceptable salt thereof as claimed inclaim 1, in which X is --(CH₂)_(n) --.
 7. A piperidine derivative or apharmacologically acceptable salt thereof as claimed in claim 2, inwhich X is --(CH₂)_(n) --.
 8. A piperidine derivative or apharmacologically acceptable salt thereof as claimed in claim 1, inwhich X is ##STR481##
 9. A piperidine derivative or a pharmacologicallyacceptable salt thereof as claimed in claim 1, in which the ring A is##STR482##
 10. A piperidine derivative or a pharmacologically acceptablesalt thereof as claimed in claim 2, in which the ring A is ##STR483##11. A piperidine derivative or a pharmacologically acceptable saltthereof as claimed in claim 1, in which X is ##STR484##
 12. A piperidinederivative or a pharmacologically acceptable salt thereof as claimed inclaim 11, in which R² is benzyl or benzyl substituted with hydroxy,lower alkoxy or halogen.
 13. A piperidine derivative or apharmacologically acceptable salt thereof as claimed in claim 1, inwhich n is
 2. 14. A piperidine derivative or a pharmacologicallyacceptable salt thereof as claimed in claim 2, in which n is
 2. 15. Apiperidine derivative or a pharmacologically acceptable salt thereof asclaimed in claim 1 in which n is
 2. 16. A pharmaceutical compositionwhich comprises the piperidine derivative as defined in claim 1 and apharmacologically acceptable carrier.
 17. A pharmaceutical compositionwhich comprises the piperidine derivative as defined in claim 2 and apharmacologically acceptable carrier.
 18. A method for treatingdementias and sequelae of cerebrovascular diseases which comprisesadministering to a patient requiring such treatment a pharmacologicallyeffective amount of the piperidine derivative as defined in claim
 1. 19.A method for treating dementias and sequelae of cerebrovascular diseaseswhich comprises administering to a patient requiring such treatment apharmacologically effective amount of the piperidine derivative asdefined in claim 2.